RESEARCH - Synovial inflammation does not change in the absence of effective treatment

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Published Online First: 13 January 2006. doi:10.1136/ard.2005.047852

ls of the Rheumatic Diseases 2006;65:990-997

© 2006 by BMJ Publishing Group Ltd & European League Against Rheumatism

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EXTENDED REPORT

Synovial inflammation does not change in the absence of effective treatment:

implications for the use of synovial histopathology as biomarker in early

phase clinical trials in rheumatoid arthritis

D Baeten1,4, J Houbiers2, E Kruithof1, B Vandooren1,4, F Van den Bosch1, A M

Boots3, E M Veys1, A M M Miltenburg2 and F De Keyser1

1 Department of Rheumatology, Ghent University Hospital, Belgium

2 Clinical Development Department and Clinical Research Department, NV

Organon, Oss, The Netherlands

3 Department of Pharmacology, NV Organon, Oss, The Netherlands

4 Clinical Immunology and Rheumatology, Academic Medical Centre/University

of Amsterdam, The Netherlands

Objectives: To determine the impact on synovial histopathology of changes in

clinical disease activity in the absence of effective treatment.

Methods: Twelve patients with active RA not receiving effective treatment

were studied over a 14 week period. Synovial biopsy specimens obtained at

baseline and week 14 were analysed by histology and immunohistochemistry.

Results: Over the course of 14 weeks, there was a trend towards a decrease

of the DAS28, with 7/12 patients being good or moderate DAS28 responders

despite the absence of effective treatment. Patients' assessment of global

disease activity and swollen joint count both decreased significantly.

Histologically, there was a decrease of lining layer hyperplasia and

lymphoid aggregates, a similar trend for vascularity, but there was no

effect on global synovial infiltration. Accordingly, there was no decrease

of the cellular infiltration with T lymphocytes (CD3, CD4, CD8), B

lymphocytes (CD20), plasma cells (CD38), dendritic cells (CD1a, CD83), and

even an increase of CD163+ sublining macrophages, with a similar trend for

CD68+ sublining macrophages. The changes in DAS28 scores in these patients

did not correlate with changes in histological variables, with the exception

of an inverse correlation with plasma cells. Remarkably, even in the DAS28

responders, no significant changes in synovial inflammatory infiltration

were noted.

Conclusions: Despite variations in global disease activity, synovial

inflammatory infiltration did not change significantly in the absence of

effective treatment. The lack of a placebo effect on synovial markers of

treatment response such as sublining macrophages can facilitate conclusive

early phase trials with small numbers of patients with RA.

http://ard.bmjjournals.com/cgi/content/abstract/65/8/990

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